Tryapanosoma brucei are parasitic protozoan that causes Human African Trypanosomiasis (HAT) or sleeping sickness, a life-threatening disease endemic in sub-Saharan regions of Africa. Current drugs available for the treatment of HAT exhibit drawbacks such as high toxicity to the hosts due to their poor parasitic cell selectivity, difficult routes of drug administration, narrow anti-trypanosomiasis spectrum and high costs of hospitalization. There is a need for potent drugs with efficient bioavailability and the ability to cross the blood-brain-barrier for treating complex stages of the disease. Tubulin plays a central role in parasitic cell growth due to their rapid rate of cell proliferation. In addition, microtubule within the flagellum of the parasite allows for locomotion via oscillations, which is vital for their survival thereby suggesting the potential advantages of tubulin inhibitors for the treatment of trypanosomiasis. Based on the differences between the parasitic and mammalian tubulins, a class of sulfonamide tubulin inhibitors previously developed as anti-cancer agents, were evaluated on T. brucei for the identification of candidates selective for parasitic cells over mammalian cells. Tubulin-inhibitor compounds evaluations suggested a difference in the colchicine-binding domains between the parasitic and mammalian cells. The predicated T. brucei tubulin structure revealed that several b sheets of the bovine and parasitic tubulin do not overlap in the colchicine domain supporting the difference in the specific binding domains that leads to selectivity of tubulin inhibitors. Several lead compounds from the sulfonamide tubulin inhibitors library (colchicine domain binders) selectively inhibited T.brucei cell growth. The pharmacophore of tubulin inhibitors with better activity on mammalian cell growth were different to those promoting T. brucei cell growth inhibition. This study therefore provides with a unique molecular scaffold that selectively targets T. brucei tubulin and has elucidated efforts for development of new lead compounds targeting tubulin for the treatment of sleeping sickness.

Identification of selective sulfonamide tubulin inhibitors as antiproliferative agents in African trypanosomiasis

246th National Meeting (2013)

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